Ciliary signaling mechanisms regulating white adipose tissue expansion

调节白色脂肪组织扩张的纤毛信号机制

• 批准号: 10503649
• 负责人: Keren Hilgendorf
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503649
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Affect; Alstrom syndrome; Architecture; Bardet-Biedl Syndrome; Biological; Body mass index; Calories; Cells; Chromatin; Cilia; Cyclic AMP; DNA Sequence Alteration; Data; Defect; Development; Diabetes Mellitus; Docosahexaenoic Acids; Equilibrium; Fatty acid glycerol esters; Female; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Human Genetics; Hyperplasia; Hypertrophy; Impairment; Inflammation; Insulin Resistance; Lead; Ligands; Link; Metabolic; Metabolic syndrome; Molecular; Monounsaturated Fatty Acids; Morphology; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Omega-3 Fatty Acids; Organelles; Overweight; Pathogenesis; Pathogenicity; Patients; Polyunsaturated Fatty Acids; Proteins; Public Health; Publishing; Research; Signal Pathway; Signal Transduction; Techniques; Thinness; Tissue Differentiation; Tissue Expansion; Tissues; chromatin remodeling; ciliopathy; comorbidity; experimental study; glucose metabolism; in vivo; innovation; lipid biosynthesis; lipid metabolism; male; mouse model; novel; pandemic disease; receptor; response; tool; trafficking

Project summary: More than 70% of adults in the USA are obese or overweight, and comorbidities, such as diabetes, pose a significant challenge to public health. In response to excess nutrients, white adipose tissue expands by both hypertrophy and de novo adipogenesis. Excessive hypertrophy is linked to insulin resistance, while mechanisms that promote adipogenesis can limit the pathogenic consequences of obesity. We recently discovered that pre- adipocytes express an antenna-like signaling organelle called the primary cilium, and that primary cilia are required for in vivo adipogenesis. We propose that primary cilia function as signaling hubs in pre-adipocytes, regulating their adipogenic potential, and hence, how white adipose tissue expands in response to caloric imbalance. Remarkably, we recently discovered that pre-adipocytes isolated from obese human and murine white adipose tissue have both fewer and shorter cilia compared to lean pre-adipocytes. To elucidate the functional importance of ciliary signaling in directing how white adipose tissue expands, we propose the following two aims: (Aim 1) Investigate how obesity affects pre-adipocyte ciliation and ciliary signaling. Pre-adipocytes in obese white adipose tissue are known to differentiate poorly due to a cell-intrinsic defect that decreases their adipogenic potential. This contributes to adipocyte hypertrophy, inflammation, and tissue dysfunction. We propose that the obese white adipose tissue microenvironment promotes pathogenic loss of pre-adipocyte primary cilia. This loss results in impairment of ciliary, pro-adipogenic signaling and decreased adipogenic potential, leading to hypertrophic expansion of white adipose tissue and contributing to impairments in glucose and lipid metabolism. Using a combination of molecular and cell biological techniques and mouse models, we will define the adipogenic signaling defects governed by obesity-induced ciliary shortening and loss, as well as the underlying mechanism. (Aim 2) Determine how human genetic mutations in ciliary genes lead to obesity and diabetes. Two ciliopathies are linked to obesity in patients, but the mutations drive opposing effects with regard to metabolic health. Both ciliopathy mutations alter the trafficking of ciliary cargo into and out of the primary cilium. We propose that these alterations modulate the composition of ciliary signaling pathways, altering the adipogenic potential of pre-adipocytes and how white adipose tissue expands. Together, experiments proposed in the two aims will establish the functional importance of pre-adipocyte cilia to white adipose tissue expansion. The proposed research constitutes a completely novel and innovative approach to identifying mechanisms underlying the loss of adipogenic potential of obese pre-adipocytes that drives pathogenesis.

项目总结： 在美国，超过70%的成年人肥胖或超重，而糖尿病等并存疾病会对 对公共卫生的重大挑战。作为对过量营养的反应，白色脂肪组织会同时扩张 肥大与新生脂肪生成。过度肥厚与胰岛素抵抗有关，而机制 促进脂肪生成可以限制肥胖的致病后果。我们最近发现，Pre- 脂肪细胞表达一种称为初级纤毛的天线状信号细胞器，初级纤毛是 体内脂肪生成所必需的。我们认为初级纤毛在前脂肪细胞中起信号枢纽的作用， 调节它们的成脂潜力，从而调节白色脂肪组织如何对卡路里做出反应 不平衡。值得注意的是，我们最近发现从肥胖的人和小鼠身上分离出的前脂肪细胞 白色脂肪组织与瘦肉前脂肪细胞相比，纤毛较少且较短。为了澄清 纤毛信号在指导白色脂肪组织如何扩张方面的功能重要性，我们提出如下建议 两个目标：(目标1)研究肥胖如何影响前脂肪细胞调节和纤毛信号。中的前脂肪细胞 众所周知，肥胖的白色脂肪组织分化较差，这是由于细胞固有的缺陷导致其 成脂潜力。这会导致脂肪细胞肥大、炎症和组织功能障碍。我们 肥胖白色脂肪组织微环境促进前脂肪细胞病理性丢失 初级纤毛。这种缺失会导致纤毛、促成脂信号的受损和成脂减少。 有可能导致白色脂肪组织的肥大扩张，并导致血糖受损 和脂类代谢。利用分子和细胞生物学技术和小鼠模型的组合，我们 将定义由肥胖引起的纤毛缩短和丢失所导致的成脂信号缺陷，以及 潜在的机制。(目标2)确定人类纤毛基因突变如何导致肥胖和 糖尿病。两种纤毛疾病与患者肥胖有关，但这两种突变的影响是相反的。 为了新陈代谢的健康。这两种纤毛病变突变都改变了纤毛货物进出初级纤毛的运输 纤毛。我们认为这些改变调节了纤毛信号通路的组成，改变了 前脂肪细胞的成脂潜力以及白色脂肪组织如何膨胀。总而言之，实验建议 在这两个目标中，将确立前脂肪细胞纤毛对白色脂肪组织扩张的功能重要性。 拟议的研究构成了识别机制的一种全新和创新的方法。 肥胖前脂肪细胞的成脂潜力丧失是导致发病的根本原因。